Sections
Tricyclic and Tetracyclic Drugs: Introduction | History and Discovery | Structure–Activity Relations | Pharmacological Profile | Pharmacokinetics and Disposition | Mechanism of Action | Indications and Efficacy | Side Effects and Toxicology | Drug–Drug Interactions | Conclusion | References
Excerpt
The tricyclic antidepressant agents hold an
important place in the history of treatments for depression. They were
the first class of antidepressant compounds to be widely used in
depression and remained the first-line treatment for more than 30
years. The observation of their activity led to theories of drug
action involving norepinephrine and serotonin. Indeed, this "psychopharmacological
bridge" suggested that alterations of these neurotransmitters
might cause depression (Bunney and Davis 1965; Prange 1965; Schildkraut 1965). The tricyclics were
extensively studied, and through this study the field developed
several principles for the management of depressive illness. For
example, in addition to understanding the need for adequate dose
and duration during acute treatment, the importance of continuation
treatment was described. The adverse events associated with these
agents required that psychiatrists become familiar with a variety of
syndromes, such as anticholinergic delirium, delayed cardiac conduction,
precipitation of acute glaucoma, and orthostatic hypotension. The
observation that tricyclic plasma concentrations varied widely stimulated
interest in understanding the metabolism of tricyclics. The field
was introduced to the concepts of polymorphisms in the mephenytoin
and debrisoquine pathways (later relabeled the cytochrome P450 [CYP] 2C19
and 2D6 pathways), which in part explained the widely varying blood
levels. Knowledge of the widely varying drug concentrations raised questions
about the relationships of clinical activity and drug concentrations.
Although effects of antipsychotics and a few other drugs on tricyclic
plasma levels had been described in the 1970s, it was the observation
of the effect of fluoxetine on desipramine coupled with the aggressive marketing
of the selective serotonin reuptake inhibitors (SSRIs) that greatly
expanded our awareness of and knowledge about drug interactions.
Finally, our knowledge of how these drugs worked became the basis
for the discovery of new drugs such as the SSRIs.